The goal of the research is to achieve a deeper understanding of in vivo nitrogen metabolism in patients with urea cycle disorders. Recent stable isotope-based studies of urea synthesis in normal individuals and in carriers of ornithine transcarbamylase deficiency (OTCD) have led us to the following hypotheses. 1: Urea precursors derived from the first- pass intestinal metabolism of dietary protein are utilized more efficiently for ureagenesis than are precursors derived from tissue metabolism. 2: As a consequence, individuals who have a compromised urea cycle activity are able to metabolize excessive dietary protein more effectively than peripherally generated precursors. This underlies the observation that the imposition of stress or infection is associated with metabolic decompensation in female OTCD carriers and mildly affected OTCD males. 3: The difference in the efficiency with which urea is synthesized from substrates of intestinal and peripheral origin is an important factor in the variable phenotype and episodic nature of OTCD. These hypotheses will be tested by carrying out stable isotopic studies of urea synthesis in normal controls and OTCD carriers. The studies will have the following specific aims. 1: Quantify urea synthesis from dietary and systemic urea nitrogen precursors in the prandial state. 2: Quantify the impact of a more prolonged period of moderate or higher protein intake on the relative utilization of endogenous and dietary nitrogen sources for ureagenesis. Urea production will be determined with [18O] urea and will be compared with simultaneous measurements of the transfer of [15N] from oral 15NH4CI, or [15N] alanine (as dietary tracers) or from intravenous 15NH4CI, [5-15N] glutamine or [15N]alanine (as tracers of endogenously generated precursors). The information will enhance understanding of nitrogen metabolism in OTCD and may lead to improvements in nutritional care by establishing the range of protein intakes to which patients can successfully adapt. In addition the results will be of broader significance to understanding nitrogen metabolism and ureagenesis during stress and infection.